Folic acid supplementation for the prevention of neural tube defects: promotion and use

Focused Revision: Policy statement on folic acid and neural tube defects

Prevention of Fetal Neural Tube Defect with Folic Acid Supplementation

Neural tube defects and folic acid in Japan: Prologue introduction ‐ Understanding of the current status of Japan and the proposal from Japanese Teratology Society

Guideline No. 427: Folic Acid and Multivitamin Supplementation for Prevention of Folic Acid–Sensitive Congenital Anomalies

Folic acid and birth malformations

Background: Previous reviews explored the association between maternal use of folic acid and multivitamin supplements and risk of neural tube defect (NTD) in children, with no definitive conclusion. These reviews had produced contradictory results, and there had been no umbrella review. Therefore, the objective of this umbrella review is to combine the inconsistent data on the effect of prenatal folic acid and/or multivitamin supplementation for the prevention of NTD in offspring. Methods: Using the PRISMA guideline, PubMed, Embase, Scopus, Web of Sciences, Cochrane Database of Systematic Reviews, Scopus, and Google Scholar reported that the effects of folic acid and/or multivitamin supplementation for the prevention of NTD in offspring were searched. The quality of the included studies was assessed using Assessment of Multiple Systematic Reviews (AMSTAR). A weighted inverse variance random-effects model was applied to find the pooled estimates. The subgroup analysis, heterogeneity, publication bias, and sensitivity analysis were also assessed. Result: Ten SRM with 296,816 study participants were included. The random-effects model analysis from 10 included systematic review and meta-analysis revealed that the pooled effect of either folic acid or multivitamin supplementation for the prevention of NTD globally is found to be 0.43 (95% CI: 0.29, 0.58) (I2 = 93.50%; p ≤0.001). In the subgroup analysis, the pooled effect was found to be 0.23 (0.09, 0.37) in folic acid group, while this estimate is 0.63 (0.53, 0.72) and 0.61 (0.46, 0.75) in groups who took multivitamin. The pooled effect of prevention of NTD was found to be 0.50 (0.34, 0.66) in SRMs aimed at occurrence prevention (primary prevention) group, while this estimate is 0.20 (−0.01, 0.41) among SRMs, which aimed at reoccurrence (secondary) prevention, and 0.61 (0.46, 0.75) among those SRMs aimed to assess the effect folic acid or multivitamin for the prevention of both occurrence and reoccurrence. The pooled effect of either folic acid or multivitamin supplementation for the prevention of NTD was found to be 0.45 (0.03, 0.87) in SRMs of observational studies, while this estimate is 0.43 (0.32, 0.54) among SRMs of randomized controlled trials. Conclusion: This umbrella review of systematic review and meta-analysis found that prenatal folic acid and/or multivitamin supplementation was associated with a 57% reduction in NTD. Participants who took folic acid supplementation were associated with a slightly higher (77%) percentage of reduction in NTD compared with those who took multivitamin (37%). Reductions of 80% and 50% were observed for reoccurrence and occurrence prevention of NTD. Reductions of 57% and 55% of NTD have been found in SRM of RCTs and observational studies. This umbrella review revealed that both folic acid and multivitamin were associated with significantly lower levels of NTD in children. Considering the incorporation of those supplements in NTD prevention strategies during the preconception period is recommended. More large-scale prospective cohort and RCTs are needed to understand the protective effect of multivitamins and/or folic acid on NTD risk addressing the molecular mechanisms and to determine the optimal dose, duration, and timing of maternal multivitamin and folic acid intake for best child NTD risk reduction.

Folate, a water‐soluble B vitamin, and its synthetic form folic acid (FA) used in fortification and supplements, are critical to human health due to their role in one‐carbon transfer reactions required for biological methylation and nucleotide biosynthesis. As such, folate deficiency has been linked to a variety of adverse health outcomes such as megaloblastic anaemia, neural tube defects, coronary heart disease and cancer among others. Corollary to this, FA supplementation has garnered a considerable amount of interest as an ideal functional food component for disease prevention. Although the benefits of FA supplementation in treatment of megaloblastic anaemia and in prevention of neural tube defects are well established, the effects of FA supplementation on other disease outcomes remain largely equivocal. In addition, an emerging body of evidence has raised concern regarding potentially serious adverse health effects of excessive FA intake, which warrant further studies. Key Concepts: Folate, a water‐soluble B vitamin, and its synthetic form folic acid used in fortification and supplements, are critical to one‐carbon transfer reactions required for DNA synthesis and biological methylation reactions. Dietary folate intake is the main source of folate for humans; inadequate dietary intake, impaired absorption or metabolism of folate, and increased folate demand and utilisation may result in deficiency. Folate deficiency has been associated with various adverse health effects including megaloblastic anaemia, neural tube defects and other congenital disorders, adverse pregnancy outcomes, neuropsychiatric disorders and cognitive decline, coronary heart disease, stroke and development of some cancers. Folic acid supplementation is effective in treatment of folate‐deficiency associated megaloblastic anaemia and in prevention of neural tube defects. The primary objective of periconceptional folic acid supplementation and mandatory folic acid fortification of the food supply, typically wheat, implemented in North American in 1998, is to prevent neural tube defects. It appears that folic acid fortification has led to up to 50% reduction in the rates of neural tube defects in North America. Folate requirements are increased throughout pregnancy due to rapid growth of the uterus, placenta and foetus, and during lactation as to maintain an adequate folate supply in breast milk for infants. Folate appears to play a dual modulatory role in colorectal carcinogenesis depending on the dose and the stage of cell transformation at the time of folate exposure. Animal studies conducted in colorectal cancer models have shown that folic acid supplementation prevents the development of cancer in normal tissues but promotes the progression of established (pre)neoplastic lesions. Animal studies have also suggested that supraphysiological supplemental doses of folic acid supplementation may promote, rather than prevent cancer development. However, folic acid intervention trials in humans have produced inconsistent results. Although folate deficiency and raised plasma homocysteine levels have been associated with increased risk of coronary heart disease in observational studies; clinical trials have reported largely null effects of folic acid supplementation on the secondary prevention of coronary heart disease. Folate status may play an important role in regulation of epigenetic determinants of gene expression such as DNA methylation relating to its critical role in the provision of S ‐adenosylmethionine, the primary methyl donor in most biological methylation reactions. Excessive folic acid intake from fortified foods and supplements has been linked to certain adverse health effects including masking of vitamin B 12 deficiency and tumour‐progression.

Folic acid (pteroylmonoglutamic acid) supplements are highly effective for prevention of neural tube defects (NTD) prompting implementation of mandatory or voluntary folic acid fortification for prevention of NTDs. We used plasma folate levels in population studies by country and year to compare effects of folic acid fortification types (mandatory or voluntary folic acid fortification policies) on plasma folate levels, NTD prevalence and stroke mortality rates. We conducted systematic reviews of (i) implementation of folic acid fortification in 193 countries that were member states of the World Health Organization by country and year, and (ii) estimated population mean plasma folate levels by year and type of folic acid fortification. We identified relevant English language reports published between Jan 1, 1990 and July 31, 2023 using Google Scholar, Medline, Embase and Global Health. Eligibility criteria were observational or interventional studies with >1000 participants. Studies of pregnant women or children <15 years were excluded. Using an ecological study design, we examined the associations of folic acid fortification types with NTD prevalence (n=108 studies) and stroke mortality rates (n=3 countries). Among 193 countries examined up to 31 July 2023, 69 implemented mandatory folic acid fortification, 47 had voluntary fortification, but 77 had no fortification (accounting for 32%, 53% and 15% of worldwide population, respectively). Mean plasma folate levels were 36, 21 and 17nmol/L in populations with mandatory, voluntary and no fortification, respectively (and proportions with mean folate levels >25nmol/L were 100%, 15% and 7%, respectively). Among 75 countries with NTD prevalence, mean (95% CI) prevalence per 10,000 population were 4.19 (4.11-4.28), 7.61 (7.47-7.75) and 9.66 (9.52-9.81) with mandatory, voluntary and no folic acid fortification, respectively. However, age-standardised trends in stroke mortality rates were unaltered by the introduction of folic acid fortification. There is substantial heterogeneity in folic acid fortification policies worldwide where folic acid fortification are associated with 50-100% higher population mean plasma folate levels and 25-50% lower NTD prevalence compared with no fortification. Many thousand NTD pregnancies could be prevented yearly if all countries implemented mandatory folic acid fortification. Further trials of folic acid for stroke prevention are required in countries without effective folic acid fortification policies. Medical Research Council (UK) and British Heart Foundation.

Papers from the Ninth International Conference on Neural Tube Defects.

The Prevention of Congenital Anomalies with Periconceptional Folic Acid Supplementation

Neural tube defects (NTDs) are common congenital neurological defects, resulting in mortality, morbidity, and impaired quality of life for patients and caregivers. While public health interventions that increase folate consumption among women who are or plan to become pregnant are shown to reduce folate-sensitive NTDs, public health policy reflecting the scientific evidence lags behind. The authors aimed to identify the types of policies applied, associated outcomes, and impact of folate fortification and supplementation on NTDs worldwide. By identifying effective legislation, the authors aim to focus advocacy efforts to more broadly effect change, reducing the burden of NTDs in neurosurgery. A systematic review was conducted exploring folate fortification and supplementation policies using the PubMed and Scopus databases. Titles and abstracts from articles identified were read and selected for full-text review. Studies meeting inclusion criteria were reviewed in full and analyzed for study design, aim, population, interventions, and outcomes. Of 1637 resultant articles, 54 were included. Mandatory folate fortification was effective at reducing folate-sensitive NTDs. Mandatory fortification also decreased hospitalization rates and deaths after discharge and increased 1st-year survival for infants with NTDs. Recommended folate supplementation also resulted in decreased NTDs; however, issues with compliance and adherence were a concern and impacted effectiveness. Folate fortification and/or supplementation resulted in decreased NTD prevalence, although more change was attributed to fortification. Dual policies may hold the most promise. Furthermore, reductions in NTDs were associated with significant cost savings over time. Both mandatory folate fortification and recommended supplementation policies were found to effectively decrease folate-sensitive NTD rates when applied. A comprehensive approach incorporating mandatory folate fortification, appropriate folate supplementation, and improved infrastructure and access to prenatal care may lead to decreased NTDs worldwide. This approach should be context-specific, emphasize education, and account for regional access to healthcare and social determinants of health. With wide implications for NTDs, associated health outcomes, quality of life of patients and caregivers, and economic impacts, policy changes can drastically improve global NTD outcomes. As caretakers of children with NTDs, the authors as neurosurgeons advocate for a comprehensive policy, the engagement of stakeholders, and a broader global impact.

Like most European countries, Norway has refrained from mandatory food fortification with folic acid to reduce the number of neural tube defects. We explored the role of folic acid and multivitamin supplements in the prevention of neural tube defects among newborn infants. We used data from the Medical Birth Registry of Norway, 1999-2013. A total of 528,220 women had 880,568 pregnancies resulting in 896,674 live- and stillborn infants, of whom 270 had neural tube defects. Relative risks were estimated with log-binomial regression. From 1999 to 2013, intake of folic acid supplements increased from 4.8% to 27.4%. Vitamin supplement use was more frequent in older, married or cohabiting women and those with lower parity, as well as women who did not smoke during pregnancy. The overall adjusted relative risk of infant neural tube defects associated with maternal vitamin intake before pregnancy relative to no intake was 0.76 (95% confidence interval: 0.53-1.10). When we divided our study period in two (1999-2005 and 2006-2013), we found a significantly reduced risk of neural tube defects overall by vitamin use in the second time period, but not in the first: adjusted relative risk 0.54 (95% confidence interval: 0.31-0.91) and 1.02 (95% confidence interval: 0.63-1.65), respectively. OVER THE FULL STUDY PERIOD, WE FOUND NO STATISTICALLY SIGNIFICANT ASSOCIATION BETWEEN VITAMIN USE AND NEURAL TUBE DEFECTS OVERALL HOWEVER, VITAMIN USE WAS ASSOCIATED WITH A SIGNIFICANTLY LOWER RISK OF NEURAL TUBE DEFECTS IN THE SECOND HALF OF THE STUDY PERIOD, 2006-2013.

The risk of a neural tube defect (NTD)‐affected pregnancy increases about 10 fold as red blood cell (RBC) folate status decreases from a sufficient status to a deficient status (&lt;340 nmol/L), with the optimal RBC folate concentration for the prevention of NTD having been recently defined as &gt;906 nmol/L by the World Health Organization. Since the implementation of mandatory folic acid fortification in the U.S. population, RBC folate concentrations have increased and NTD prevalence has decreased about35%. There are three primary sources of folic acid in the U.S. diet: folic acid supplements (typically 400 μg ‐ 1,000 μg per dose), ready‐to‐eat breakfast cereals (allowed but not required to include 400 μg per serving) and cerealgrain flour labeled as enriched (140 μg per 100g; resulted in ~140 μg increase in daily average usual intake). It is critical to determine if this demonstrated effective intervention has reached its full potential. To determine if women in the U.S. were still at risk of folate sensitive NTDs even in the presence of folic acid fortification we used RBC folate concentration distributions from the 2007–2012 National Health and Nutrition Examination Survey (NHANES) among U.S. women of childbearing age (12–49 years) to estimate NTD prevalence by source of folic acid intake. We applied a prediction model developed using Bayesian methods to estimate the risk of NTD‐affected pregnancies at specific RBC folate concentrations. The overall predicted NTD risk was 6.9 per 10,000 births (95%uncertainty interval [UI] 5.0–9.0) based on a median RBC folate concentration of 1220 nmol/L (log of the variance σ =0.400). RBC folate concentrations were higher for supplement users compared to non‐users, however, there was no difference in their predicted NTD risk. This is consistent with the NTD risk observed between folic acid supplement users and non‐users among existing epidemiological studies. However, women whose only reported source of folicacid was cereal grain products labeled as enriched had RBC concentrations (median1075 nmol/L) that suggest significantly elevated predicted NTD risks (8.8 NTD sper 10,000; 6.7–11.1 95% uncertainty interval) compared to women who consumed additional sources of folic acid (i.e. ready‐to‐eat cereal and/or supplements)in their diet (median NTD prevalence: 4–6 per 10,000 births). Population level estimated NTD prevalence was driven by slight shifts in distribution at the lower RBC folate concentration because NTD risk increases very rapidly with decreasing folate concentrations. Additional analyses are underway to determine usual folic acid intake among women with optimal RBC folate concentrations. Folate‐sensitive NTD prevention interventions could be considered to target U.S. women of reproductive age consuming cereal grain products labeled as enriched as their only source of folic acid.Support or Funding InformationNo external support.

Background/Aims: To review the main results of intervention trials which showed the efficacy of periconceptional folic acid-containing multivitamin and folic acid supplementation in the prevention of neural-tube defects (NTD). Methods and Results: The main findings of 5 intervention trials are known: (i) the efficacy of a multivitamin containing 0.36 mg folic acid in a UK nonrandomized controlled trial resulted in an 83–91% reduction in NTD recurrence, while the results of the Hungarian (ii) randomized controlled trial and (iii) cohort-controlled trial using a multivitamin containing 0.8 mg folic acid showed 93 and 89% reductions in the first occurrence of NTD, respectively. On the other hand, (iv) another multicenter randomized controlled trial proved a 71% efficacy of 4 mg folic acid in the reduction of recurrent NTD, while (v) a public health-oriented Chinese-US trial showed a 41–79% reduction in the first occurrence of NTD depending on the incidence of NTD. Conclusions: Translational application of these findings could result in a breakthrough in the primary prevention of NTD, but so far this is not widely applied in practice. The benefits and drawbacks of 4 main possible uses of periconceptional folic acid/multivitamin supplementation, i.e. (i) dietary intake, (ii) periconceptional supplementation, (iii) flour fortification, and (iv) the recent attempt for the use of combination of oral contraceptives with 6S-5-methytetrahydrofolate (methylfolate), are discussed. Obviously, prevention of NTD is much better than the frequent elective termination of pregnancies after prenatal diagnosis of NTD fetuses.

In memoriam: Dr. Andrew Czeizel.